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5-Aminolevulinic acid suppresses the effector function of feline lymphocytes by reducing the mitochondrial membrane potential

ABSTRACT: 5-Aminolevulinic acid (ALA) is an endogenous amino acid in mammalian cells; it is the first amino acid in the heme biosynthesis pathway occurring in the mitochondria. ALA possesses anti-inflammatory properties by inducing heme oxygenase (HO)-1 expression and releasing heme metabolites in humans and mice. We previously showed that ALA enhances the production of interferon-gamma (IFN-γ) and interleukin-17A in concanavalin A (ConA)-stimulated canine lymphocytes. However, the effects of ALA on feline lymphocytes remain to be investigated. In this study, we demonstrated that ALA-induced HO-1 expression and decreased IFN-γ production in ConA-stimulated feline lymphocytes. Comprehensive RNA sequencing analysis revealed that the Activating transcription factor 4 (ATF4) signaling pathway was inhibited by the addition of ALA. Moreover, we confirmed that ALA decreased ATF4 protein expression. Furthermore, the addition of ALA inhibited the phosphorylation levels of AKT and induced mitochondrial dysfunction in activated lymphocytes. Thus, ALA may suppress the effector function of feline lymphocytes via mitochondrial metabolism, thereby representing a novel mechanism in ALA research.

ORGANISM(S): Felis catus

PROVIDER: GSE255919 | GEO | 2025/02/16

REPOSITORIES: GEO

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The effect of 5-aminolevulinic acid on canine peripheral blood mononuclear cells

Project description:5-aminolevulinic acid (ALA) is one of the natural amino acids and a product of the first heme synthesis pathway in mitochondria. Recently, a supplement containing ALA is available in Japan and used for the purpose of the enhancement of ATP synthesis via mitochondrial activity. In humans, the immunomodulatory effect of ALA has attracted attention as a new function of ALA, and its application to cancer, inflammatory disease, and autoimmune diseases are being investigated. In the present study, to evaluate the effects of ALA on canine immunity, we performed in vitro studies using peripheral blood mononuclear cells (PBMC) from healthy dogs. Heme oxygenase-1 protein was expressed in Madin-Darby Canine Kidney cells and PBMCs treated with 5-ALA and ferrous sodium citrate (SFC), which showed that ALA works in dogs as well as humans. When PBMCs were stimulated with concanavalin A (ConA), the addition of ALA resulted in a significant increase in interferon-gamma (IFN-γ) produced by ConA-stimulated PBMCs. A comprehensive genetic alteration using next-generation RNA sequences (RNA-seq) was performed. From the result of RNA-seq, ALA enhanced the gene expression of T cell immunity including Th1, Th2, and Th17 subsets. In particular, the IL-17 signaling pathway was significantly upregulated. Then, we confirmed that ALA promoted the production of interleukin (IL)-17A in ConA-stimulated PBMCs. Together, these findings reveal that ALA promotes heme synthesis in mitochondria and enhances ConA-induced T cell immune responses in canine PBMCs.

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Expression data from Arabidopsis thaliana seedlings with reduced synthesis of 5-aminolevulinic acid

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The novel heme-dependent inducible protein, SRRD regulates heme biosynthesis and circadian rhythms

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